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"The benefit of corticosteroids in severe sepsis and septic shock remains controversial," Djillali Annane, MD, from Hôpital Raymond Poincaré, Assistance Publique-Hôpitaux de Paris in Paris, France, and colleagues. "We performed a new systematic review of the effects of corticosteroids on 28-day mortality in patients with severe sepsis and septic shock, and we examined, as a secondary objective, whether the dose or duration of treatment with corticosteroids influenced patients' outcomes."

The reviewers searched CENTRAL, MEDLINE, EMBASE, and LILACS databases through March 2009, looking for randomized and quasi-randomized trials of corticosteroids vs placebo or supportive treatment in adults with severe sepsis and septic shock, using the consensus definition of the American College of Chest Physicians and Society of Critical Care Medicine. Bibliographies of retrieved articles and proceedings of major meetings were also searched for suitable studies, and trial investigators were contacted for additional information.

All reviewers determined eligibility of the retrieved studies for the meta-analysis, and 1 reviewer extracted data. Whenever possible, the other reviewers and the trials' investigators checked the extracted data. The trials' investigators also provided some unpublished data. The main endpoint for this review was 28-day mortality rate.

Identified studies with methodologic quality sufficient to pool in a meta-analysis were 17 randomized trials enrolling a total of 2138 patients and 3 quasi-randomized trials including 246 patients.

For treated vs control patients, there was no difference in 28-day mortality rate, which was 388 (35.3%) of 1099 vs 400 of (38.5%) 1039 in randomized trials (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.71 - 1.00; P = .05; I² = 53% by random-effects model) and 28 (23.1%) of 121 vs 24 (19.2%) 125 in quasi-randomized trials (RR, 1.05; 95% CI, 0.69 - 1.58; P = .83).

In a subgroup of 12 trials looking at the effects of prolonged low-dose corticosteroid treatment, 28-day mortality rate for treated patients vs control patients was 236 (37.5%) of 629 vs 264 (44%) of 599 (RR, 0.84; 95% CI, 0.72 - 0.97; P = .02). In this subgroup, this treatment was associated with improved shock reversal at 28 days (6 trials; 322/481 [66.9%] vs 276/471 [58.6%]; RR, 1.12; 95% CI, 1.02 - 1.23; P = .02; I² = 4%) and decreased length of stay in the intensive care unit (ICU) by 4.49 days (8 trials; 95% CI, –7.04 to –1.94; P < .001).

Adverse effects of gastroduodenal bleeding, superinfection, and neuromuscular weakness were not increased by prolonged low-dose corticosteroid treatment in this subgroup. However, risks were higher in treated patients for hyperglycemia (9 trials; 363/703 [51.6%] vs 308/670 [46%]; P < .001; I² = 0%) and hypernatremia (3 trials; 127/404 [31.4%] vs 77/401 [19.2%]; P < .001; I² = 0%).

"Corticosteroid therapy has been used in varied doses for sepsis and related syndromes for more than 50 years, with no clear benefit on mortality," the reviewers write. "Since 1998, studies have consistently used prolonged low-dose corticosteroid therapy, and analysis of this subgroup suggests a beneficial drug effect on short-term mortality."

Limitations of this review include quality of evidence judged as moderate vs high.

"According to these findings, corticosteroids should be considered at a daily dose of 200 to 300 mg of hydrocortisone (or equivalent) as intravenous bolus or continuous infusion," the review authors conclude. "Although evidence is not particularly robust, we suggest that treatment should be given at full dose for at least 100 hours and only in adults with vasopressor-dependent septic shock....The evidence accumulated from 7 trials uniformly does not support the use of a short course of high dose corticosteroids in severe sepsis or septic shock."

In an accompanying editorial, Roman Jaeschke, MD, MSc, from McMaster University in Hamilton, Ontario, Canada, and Derek C. Angus, MD, MPH, from University of Pittsburgh in Pittsburgh, Pennsylvania, note the uncertainty of the underlying evidence.

"Based on current evidence, physicians can and should counsel the family of a patient with septic shock that the decision to use corticosteroids (or, for that matter, to use activated protein C or right heart catheter) is not black and white and that reasonable people may reach different conclusions about exactly what is the correct decision," Drs. Jaeschke and Angus write. "Admitting this uncertainty does not necessarily burden patients and families with the final decision, but they deserve to know that their physicians are not sure."

This review was initially developed within the Cochrane Collaboration Infectious Diseases Group, supported by the UK Department for International Development. Drs. Jaeschke and Angus have participated in the development of clinical practice guidelines regarding steroid use in sepsis. Dr. Angus has also disclosed various financial relationships with Wyeth-Ayerst, Roche Diagnostics, Biomerieux, Brahms Diagnostica, Eisai, Takeda, Novartis, Bayer, Eli Lilly, and Eisai.

JAMA. 2009;301:2362-2375, 2388-2390.

Clinical Context

Study Highlights

• The reviewers conducted a search on the CENTRAL, MEDLINE, EMBASED and LILACS databases and the reference lists of articles and authors were also contacted.
• Included were RCTs and quasi-RCTs of corticosteroids vs placebo or supportive treatment in adult patients with severe sepsis/septic shock per the American College of Chest Physicians/Society of Critical Care Medicine consensus definition.
• 4 authors independently extracted data, and quality of studies was rated.
• Primary outcome was 28-day all-cause mortality rate.
• Secondary outcomes were hospital mortality rates, ICU mortality rates, and adverse effects.
• 34 RCTs were identified, of which 22 met inclusion criteria.
• 6 trials were multicenter and 1 was multinational.
• 7 included patients with both septic shock and severe sepsis, 2 with severe sepsis, 1 with early acute respiratory distress syndrome, and the remaining had patients with septic shock.
• 9 trials investigated prolonged course of low-dose corticosteroids, and 7 investigated a short course of high-dose corticosteroids.
• 28-day mortality rate was reported in 12 trials and obtained for 3 more trials.
• 3 trials reported 14-day mortality rate, 6 reported ICU mortality rate, and 3 reported hospital mortality rate.
• Data were computed from 17 RCTs (n = 2138) and 3 quasi-RCTs (n = 246).
• The 28-day mortality rate for treated patients vs control patients was 35.3% vs 38.5% (RR, 0.84; P = .05) in RCTs and 23.1% vs 19.2% in quasi-RCTs (RR, 1.05; P = .83).
• There was little heterogeneity across studies.
• 7 trials reported a short course of high-dose corticosteroids (n = 1043), and 28-day mortality rate was 33.2% for treated patients vs 31.5% for control patients (RR, 0.94).
• For ICU mortality, the RR was 0.81 for prolonged low-dose corticosteroids (40.5% vs 45.6%, not significantly different).
• For hospital mortality, 15 trials (n = 1672) reported a mortality rate of 38.7% for treated patients vs 44.0% for control patients (RR, 0.83; P = .05).
• When shock reversal by 7 days was used as an outcome, the rate was 66.9% for treated patients vs 58.6% for control patients (RR, 1.12; P = .02).
• Length of ICU stay was reduced by 4.49 days in 8 trials without an increase in the risk of bleeding, superinfection, or neuromuscular weakness.
• The rates of gastroduodenal bleeding, superinfections, and neuromuscular weakness were not significantly higher in the treated groups.
• Hyperglycemia was higher in the treated groups (51.7% vs 45.6%; RR, 1.16; P < .001) as was hypernatremia (31.4% vs 19.2%; RR, 1.61; P < .001).
• The authors concluded that use of corticosteroids in patients with septic shock and sepsis was associated with improved survival rates with reduced 28-day all-cause mortality and hospital mortality rates.

Clinical Implications

• Use of corticosteroids in patients with severe sepsis and shock is associated with reduced 28-day and hospital mortality rates.
• Use of corticosteroids in patients with severe sepsis and shock is associated with an increased rate of hypernatremia and hyperglycemia.